PROJECT DESCRIPTION Cytomegalovirus (CMV) inflammatory disease of the gastrointestinal tract is a major complication of immunosuppression in Veterans. In addition, CMV can induce relapse, exacerbate mucosal inflammation, and cause glucocorticoid resistance in Veterans with inflammatory bowel disease (IBD). To elucidate the pathogenesis of CMV mucosal inflammation, we have shown that blood monocytes are the exclusive source of intestinal macrophages and that pro-inflammatory monocytes recruited to the gut mucosa differentiate in the presence of extracellular matrix (stroma)-derived TGF-2 into non-inflammatory lamina propria macrophages. In the setting of CMV infection, we hypothesize that (1) CMV infection of monocytes induces resistance to stromal down-regulation; (2) CMV infection of monocytes reverses stromal (TGF-2- mediated) down-regulation by activating NF-:B signaling, resulting in the transcription of pro-inflammatory genes and, after a second stimulus, the release of pro-inflammatory cytokines; and (3) CMV infects intestinal and colonic macrophages and reverses the cells' inflammation anergy. To address these hypotheses, we propose three Specific Aims: (1) Determine whether CMV infection of blood monocytes induces resistance to stromal down-regulation of monocyte pro-inflammatory function. (2) Determine whether CMV infection of blood monocytes and intestinal and colonic macrophages activates NF-:B signal transduction, overriding stromal down-regulation of pro-inflammatory function. (3) Determine whether CMV infection and inflammatory responses in monocytes and intestinal and colonic macrophages are enhanced in the setting of inflamed mucosa.